The annual Gerhard Schmidt Memorial Lecture, on its 15th year after it was established in 2002, will be held on September 27, Wednesday, 4 pm at Behrakis auditorium,Jaharis building. The lectureship was established originally by the Department of Biochemistry, now a part of the Developmental, Chemical & Molecular Biology Department at the Tufts University School of Medicine, in memory of Gerhard Schmidt, M.D., to commemorate his life and contributions to the fields of nucleic acid and phospholipid research.
Dr. Schmidt joined the Tufts faculty in 1940 after migrating to the U.S. from Europe due to the increasingly tense political climate in the 30s. While he was working at the University of Frankfurt, Dr. Schmidt published a seminal paper describing enzymatic processes of deamination. In 1933, when Dr. Schmidt became aware of the Nazis’ intentions of purging “Jewish science” in his department, he fled to Italy. After a series of short-term fellowships took him to Naples, Stockholm and Florence, as well as Kingston, Ontario, New York and St. Louis before coming to Boston (source). Soon after his arrival, Dr. Schmidt published a milestone paper where he described a novel technique to determine the DNA and RNA quantities in tissues. In 1973, Dr. Schmidt was awarded an emeritus position at Tufts and the same year, he was elected to the National Academy of Sciences. Until he passed away on April 24, 1981, Dr. Schmidt had continued to regularly work in his laboratory despite his poor health in his latter years. Besides being a dedicated and hard-working scientist, Dr. Schmidt was an avid supporter of the arts, particularly chamber music and literature; he was also a fellow of the American Academy of Arts and Sciences.
This year, Judith Campisi, PhD, will deliver the Schmidt memorial lecture titled “Cancer and Aging: Rival Demons?”. Dr. Campisi is a world leader in the field of aging research, and currently is a professor of biogerontology at the Buck Institute for Research on Aging. Dr. Campisi received her B.A. in Chemistry in 1974 and Ph.D. in Biochemistry in 1979 from SUNY Stony Brook. She did her post-doctoral training at Dana Farber Cancer Insitute, before moving on to join the Biochemistry Department at Boston University School of Medicine in 1984. From there, Dr. Campisi moved on to Lawrence Berkeley National Laboratory (LBNL) where she headed the Carcinogenesis & Differentiation group, and the Department of Cell & Molecular Biology before taking on the position of co-head of Center for Research and Education on Aging in 1999.
She is also a member of the SENS Research Foundation Advisory Board (a non-profit that seeks to develop rejuvenation biotechnology) and an adviser at the Lifeboat Foundation (non-profit NGO that wants to harness technological advancements to “save humanity from existential risks”). She is also the co-editor in chief of the scientific journal Aging, a fellow of the American Association for the Advancement of Science (AAAS), and recipient of the Longevity Prize from the Ipsen Foundation and the Olav Thon Foundation prize (source), besides multiple other awards and fellowships.
Dr. Campisi is mostly known for her work on the role of aging on a variety of disease conditions, including cancer. She has worked extensively on senescent cells and how they may also disrupt normal physiological functions in tissues thus contributing to cancer progression. She has also described the hallmarks of senescence, including the senescence-associated secretory phenotype. She has described her research interests as following – “Aging is controlled by genes and the environment, and poses the largest single risk for developing a panoply of diseases, both degenerative (e.g., Alzheimer’s disease, osteoporosis, cardiovascular disease) and hyperproliferative (e.g., cancer). Why do organisms age, and why do these diseases rise exponentially with age? My laboratory aims to understand the molecular and cellular basis of aging in mammals.” (source)
For more information on her research, check out the following resources –
This month I present, for your reading pleasure, excerpts from my interview with Nafis Hasan from CMDB. Nafis and I had a remarkably wide-ranging conversation covering existential philosophy, cultural differences between Bangladesh and the US, the exquisite symmetry between ecology and cell biology, and current controversies in carcinogenesis research. I can only hope to capture in the space below a mere whisper of his deeply-considered intellectual convictions and passion for social justice. Fortunately, Nafis has also authored an editorial on Science Activism in this very issue, and I strongly urge you, dear reader, to check that out next!
AH: Where did you grow up?
NH: I grew up in the house that my father and his brothers built in Dhaka, Bangladesh, and moved to the U.S. when I was 18. Most of my dad’s siblings and their families lived with us in Dhaka. As kids, we didn’t really have the notion of “privacy” for the longest time: the elders would each get a room and the kids would sleep in the living room on a big mattress. My cousins and I would all get into trouble at the same time… it was fun!
AH: Have you had any opportunities to travel around the States?
NH: For F1 visa (student visa) holders, you have a 3-month window where you have to find a job or get into school. After graduating from Lafayette College [in Easton, Pennsylvania], I thought, “If I have to leave the country, I might as well see it.” So when one of my friends said, “Let’s do a road trip,” I said “Let’s do it!” We started from Pennsylvania, went down to Virginia, our first stop was Shenandoah – I had actually never been camping before that, it was all a very new experience. We had two American kids, a Colombian kid, and a kid from South Africa… It was very liberating, and I started to see the country as it really is. At the same time, on the road, I was interviewing for jobs. I remember doing a job interview [by video phone] at a McDonalds in Idaho. I borrowed a shirt from one of my friends who dresses nicer than I do, since the interviewer could only see the top half of me… Over the course of two months, I think I applied to 200 jobs. Finally, I ended up getting a research tech job at Thomas Jefferson University in Philly.
AH: What was it like adjusting to American culture?
NH: When I came to America, I had no idea what to expect, I had only heard things from my cousins who came here for college and what was on TV. One thing that I had in my mind was that I was going to try and meet as many people of different nationalities as I can. But there was a big cultural divide, how they grew up versus how I grew up. I think the road trip really helped me to understand the diversity of American people and especially during these times when people are so polarized, I reach out to that experience. We grew up seeing this version of America as the land of opportunity, the land of freedom, but America is not the government, is not their foreign policy, is not the consumerism that has taken over the world… America is more about the people that you meet here, and that’s how I see the country. America encapsulates the dichotomy of homogeneity versus heterogeneity, and I think that’s so beautiful.
AH: When did you begin to discover your interest in biology research?
NH: In Bangladesh I went to a private school that taught everything in English. The division of sciences starts in 7th grade, and biology was definitely the most interesting to me. At the same time, I was caught up in the process of deconstructing my religious identity, because I was reading biology which has hard facts about how your body works, which calls into question how life was created… I found that more fascinating than having a set answer imposed by some superior being.
AH: How did you choose your field of study for grad school, and why is it so interesting?
NH: I started reading a lot of scientific nonfiction, presenting cancer as a very complex biological phenomenon, which was fascinating to me. I also had a solid foundation in breast cancer by the time I applied for grad school and I wanted to pursue that… I had seen lots of tumors, but no mammary glands. The more I learn about the mammary gland, the more I am fascinated by it. It develops throughout life: initially it’s just a branched structure that looks like sticks; when you get pregnant, it almost flowers, with grape-like clusters that come up through alveologenesis and these alveoli then revert back to the branched structure after weaning. It’s comparable to how trees shed leaves in the Fall, except in reverse: this course of nature – the seasons that you see – the same dynamic is there in animal tissue. And all of this is happening through the lifetime, after the majority of the organs are already fully developed!
AH: What is one of the big challenges or controversies in your field at the moment?
NH: Traditionally, cell culture is done in two dimensions, on plates that are usually plastic – and plastic is not a natural substrate for cells to grow on, so you can’t recapitulate the same 3D environment where the cells are growing inside an organism. You can either try to mimic the natural environment as much as possible, or try to make a scaffold that is biocompatible… Cells need to be able to manipulate their environment, just as the environment should be able to provide them with physical or chemical cues to make them grow or organize in certain ways. Our lab has a very organic approach to it: we do 3D cultures in type 1 collagen, the predominant structural protein found in the mammary gland stroma. We believe that “organicism is greater than reductionism.” This is where we’re at odds with a lot of others in the cancer field, where reductionism is still the predominant philosophy. And we’re not saying it’s bad! It’s just insufficient to explain carcinogenesis.
In January 2015, President Obama announced the launch of the “Precision Medicine Initiative”, proclaiming it to usher in “a new era of medicine that makes sure new jobs and new industries and new lifesaving treatments for diseases are created right here in the United States.” In addition, he remarked that the promise of this initiative laid in “delivering the right treatments, at the right time, every time to the right person”. This initiative, with bipartisan support in the Congress, provided a total of $215 million investment in 2016 for the NIH, along with the FDA and the Office of the National Coordinator for Health Information Technology (ONC), with a large portion of the money ($70 million) awarded to NCI to “scale up efforts to identify genomic drivers in cancer and apply that knowledge in the development of more effective approaches to cancer treatment”. The initiative doesn’t stop at the genome level, as Dr. Francis Collins, Director of the NIH, pointed out in an interview with PBS News Hour, and is meant to provide information about environmental exposures, lifestyle choices and habits and pretty much everything that can affect one’s health. Given the mass of information that will be generated (the initiative aims to enlist 1 million volunteers for its cohort), it is no surprise that patient privacy issues, as well as database infrastructure, are major concerns in this mammoth undertaking.
In addition to this initiative, the US government also launched its “Cancer Moonshot Program” a year later in January 2016. This program, under the leadership of Vice President Joe Biden, and with the help of an expert panel, the “Cancer Moonshot Task Force”, aims to “make more therapies available to more patients, while also improving our ability to prevent cancer and detect it at an early stage.” Since cancer is widely accepted to be a genetic disease, it seems fitting to serve as the poster child for an initiative that aims to cure and prevent diseases based on tailoring therapy for an individual using personal genetic information.
Tied to these two initiatives is also the latest approach to clinical trials at the NCI, commonly termed as “basket trials”. Based on findings from exceptional case reports where patients treated with drugs not commonly used for that type of cancer, the NCI was encouraged to try out drugs traditionally reserved for particular types of cancer for the ones that they weren’t developed for; thus, the Molecular Analysis for Therapy Choice (MATCH) and the Molecular Profiling-Based Assignment of Cancer Therapy (MPACT) trials were incorporated into the Precision Medicine initiative. The NCI-MATCH trial aims to sequence tumor biopsy specimens from ~6,000 patients to identify mutations that will respond to targeted drugs selected for the trial; these drugs are already approved by the FDA for certain cancer types or are being tested in other clinical trials. On the other hand, the MPACT trial will compare whether patients with solid tumors fare better with targeted therapy vs non-targeted therapy.
Despite the initial fanfare, the recently released NCI-MATCH major interim analysis report does not paint a pretty picture for the trial’s outcome. While the enrollment was higher than expected (795 people registered in first 3 months compared to the projected 50 patients/month) and the labs were able to sequence most of the tumors (87%), it was also found that “most of the actual mutation prevalence rates were much lower than expected based on estimates from The Cancer Genome Atlas and other sources”. In fact, the overall expected mutation match rate was adjusted to 23% for the 24 treatment arms in the study as it continues.
While no endpoint has yet been reached to draw conclusive remarks about this trial, data available from other clinical trials that have taken a similar approach do not seem favorable. In the SHIVA trial, a randomized phase II trial carried out in France where 99 patients were treated based on identified mutation(s) compared to 96 patients treated with drugs of their physicians’ choice, median progression-free survival was 2.3 and 2 months, respectively. Current clinical data on patients with relapsed cancers, a major focus of the MATCH trial, do not seem favorable either. As Dr. Vinay Prasad, a haematologist-oncologist at Knight Cancer Institute, points out, only 30% of such patients respond to drugs based on biological markers and the median progression-free survival is 5.7 months. Based on this response rate, he estimated only 1.5% of patients with relapsed and refractory solid tumors to benefit from the precision medicine approach.
In a review of current clinical trials and past trials that have used the targeted therapy approach, Tannock & Hickman (NEJM, 2016) warn about the limitations of such an approach – heterogeneity and clonal evolution of cancer cells when challenged with targeted therapy, the inconsistency between expected and clinically achievable levels of inhibition of candidate molecules and of course, the efficacy of such therapies compared to currently available, standard but effective therapies such as aromatase inhibitors for breast cancer. While one can argue that heterogeneity in tumors can be countered with combination targeted therapy, the authors point out that “combinations of molecular targeted agents that target different pathways have often resulted in dose reduction because of toxic effects… in a review of 95 doublet combinations in 144 trials, approximately 50% of the combinations could use the full doses that were recommended for use as single agents, whereas other doublets required substantial dose reductions.” Even if it is possible that intratumoral heterogeneity can be countered with combination targeted therapy, a much-overlooked point in this initiative is the cost of such treatment strategy, considering the exorbitant costs of targeted cancer therapy. There already exists a disparity among cancer patients from a socio-economic standpoint and this initiative does little to address how to bridge such a gap. Questions such as how many drugs will a patient have to take, especially in cases of tumors that are highly heterogeneous, such as glioblastoma multiforme and how that would affect the living standard of a patient need to be considered before heralding a victory for the precision oncology approach even if the MATCH trial outcomes are favorable.
In another recent study, Dr. Victor Velculescu and his team from Johns Hopkins showed that sequencing only tumor genetic data can lead to false positives. After analyzing 815 cancer patients’ tumor sequencing data and comparing that data to the one from the patients’ healthy tissue, they found that 65% of genetic changes identified with tumor-only sequencing data were unrelated to the cancer and therefore, “false positives”. The team also found that 33% of mutations, which are targets of currently available drugs, were also false positives when the patient’s germline genome was compared to the tumor genome; this affected 48% of the patients in their cohort.
The paradigm behind the MATCH trial, and in general the Precision Medicine initiative, seems to be blind to an obvious aspect of biology – context matters, and more so, in case of mutations that are deemed to be “carcinogenic”. As outlined in a recent paper by Zhu et al (Cell, 2016) and the famous “bad luck” paper by Tomasetti and Vogelstein, it appears that the stem cells and their differential regenerative properties in different tissue types are responsible for the differential rates of carcinogenesis in various tissue types, a finding that again, buttresses the idea that tissue specificity matters. In fact, Iorio et al (Cell, 2016) was able to show just that in the context of pharmacogenomic interactions of currently available cancer drugs with data available from patient samples in the TCGA and other databases. Using a big data and machine learning approach, the authors developed a logic-based model that would predict the efficacy of any drug that is either approved or undergoing clinical trials against the mutation it is intended for in different cancer types ,which is essentially the basis of the MATCH trial. Surprisingly, it appeared that tissue specificity determined the pharmacological agents’ effects on the intended molecular targets; more specifically, only one drug interaction (out of 265 drugs tested) was found to be significant in multiple cancer types, which may sober up the expectations from the MATCH trial outcome. Therefore, using a blanket approach to target mutations in various tissue types without consideration to their environments can seem futile in the light of such findings.
The evidence from all these basic science and clinical studies raise the question of whether precision medicine is doomed to fail. While the gene-centric view of disease etiology have deepened over the years since the completion of the Human Genome Project, does this evidence point to the necessity of another paradigm in our understanding of cancer and other complex diseases, whose cures have been presumed to lie in genetic aberrations and molecular targets? An even more concerning question, relevant in this era of big data, is whether we actually understand what the data is telling us, as the prominent cancer researcher, Dr. Robert Weinberg, admits that “while data mining, as it’s now called, occassionally flags one or another highly interesting gene or protein, the use of entire data sets to rationalize how and why a cancer cell behaves as it does is still far beyond our reach”. A strong critic of the initiative, Dr. Michael Joyner from Mayo Clinic, opines that while “hundreds of genetic risk variants with small effects have been identified…But for widespread diseases like diabetes, heart disease and most cancers, no clear genetic story has emerged for a vast majority of cases” and that “when higher-risk genetic variants are found, their predictive power is frequently dependent on environment, culture and behavior”.
The success of Precision Medicine Initiative, and in particular, the precision oncology approach, ultimately rests on whether it can stem and curb deaths resulting from cancer and other complex diseases, based on molecular targeted therapy. Unfortunately, it appears that large scale public health initiatives have done more to that end (e.g. – tobacco control has largely cut down rates of lung cancer incidence, diet and exercise can cut down the risk of converting pre-diabetes to diabetes by nearly two-thirds), compared to what targeted therapy have achieved. However, it seems that such public health success was overlooked by the Cancer Moonshot panel as in February 2016, right after the program was announced, public health researchers across the country had to urge the Vice President to make prevention a bigger focus in controlling cancer incidence in the population, rather than just trying to find a cure. This approach should have been incorporated into a billion-dollar initiative by default, one would think, but this didn’t seem to be the case and one must wonder why.
In order for this huge, publicly-funded initiative to achieve more than just lukewarm outcomes and to actually become a breakthrough it is promised to be, the Precision Medicine initiative needs to break free of the gene-centered tunnel vision and incorporate all factors that affect an individual’s health, such as lifestyle choices and environmental exposures, as Dr. Collins boasted it to be. While this initiative is only at its infantile stage, changes based on clinical trial and basic science evidence should be made early enough so that favorable outcomes can be achieved and does not require the government to stage another public bailout as it did for the failing banks and wall street corporations back in 2008 when they were deemed to be “too big to fail”.
On 29th October of this year, the Lancet Oncology published a report on the carcinogenicity of red meat and processed meat . The Working Group, consisting of 22 scientists from 10 different countries, recommended to the International Association of Research on Cancer (IARC) (part of the World Health Organization) to classify processed meat to be “carcinogenic to humans” (Group 1) and red meat to be “probably carcinogenic to humans” (Group 2). These recommendations were made after evaluation of more than 800 epidemiological studies.
Since the publication of the report, mainstream media has picked it up with a fervor that painted the report with a facade of novelty. However, as Tufts University’s very own Dariush Mozaffarian (Dean of Friedman School of Nutrition Science) pointed out in an interview with National Public Radio (NPR), this report only served to solidify what has been known for quite a while now.
Given the significant associations made between cancer risk and consumption of red and processed meat, what is the public supposed to do?
Besides following Chik-fil-A’s advice, here is what you need to know before you decide get well done with meat.
Red meat include beef, lamb, pork, goat. Processed meat include anything that has been cured, salted, smoked, or preserved in some way, e.g. – sausages, bacon, hot dogs, etc.
What did the IARC find? Colorectal/bowel cancer showed the strongest association with high red and processed meat consumption. Positive associations were also seen between red meat consumption and pancreatic and prostatic cancers, and between processed meat consumption and cancer of the stomach .
How scary are these findings? The Working Group found that there is a 17% increased risk of colorectal cancer for those who ate the most processed and red meat compared to those who ate the least . Is this number really big? As Cancer Research UK blogged, the “17%” represents a relative risk; out of every 1000 people in the UK, 61 people develop bowel cancer at some point in their lives compared to about 56 cases per 1000 low meat-eaters. Therefore, according to the analysis, a 17% increased risk translates to 66 people per 1000 would develop bowel cancer at some point in their lives .
However, labeling processed meat as cancer causing and red meat as probably cancer causing does little to soothe our worries. But! As Cancer Research UK points out, IARC does “hazard identification” and not “risk assessment” . Therefore, IARC classifications can only provide a qualitative assessment and does not tell us how potent something is in causing cancer. This is exemplified when red/processed meat is compared to tobacco, which is also classified into Group 1. In the UK, excessive consumption of red/processed meat resulted in 3% of all cancer cases annually whereas smoking caused 19% of all annual cancer cases.
How to balance your bacon Dariush Mozaffarian suggests no more than, one or two servings of processed meat per month and of red meat per week. For more customizable options, check out the awesome infographic from Cancer Research UK below –
So, as with everything, MODERATION IS KEY! Unless, of course you are Ron Swanson.
1. Bouvard, V et al 2015 Lancet Oncology. doi:10.1016/S1470-2045(15)00444-1.
2. Dunlop, C. 2015. Processed meat and cancer- what you need to know. Cancer Research UK, Science blog. http://scienceblog.cancerresearchuk.org/2015/10/26/processed-meat-and-cancer-what-you-need-to-know/
3. Aubrey A. World Health Organization Report Links Red, Processed Meats to Cancer. National Public Radio. http://www.npr.org/2015/10/26/452012186/world-health-organization-report-links-red-processed-meats-to-cancer
4. Bartlett, E. 2015. The World Health Organisation says bacon is carcinogenic and right-wingers think it’s a Muslim conspiracy. Independent. http://i100.independent.co.uk/article/the-world-health-organisation-says-bacon-is-carcinogenic-and-rightwingers-think-its-a-muslim-conspiracy–ZJLDa_0B_l